The preparation of well-defined microspheres of controlled composition is of great importance, because of the potential use of such particles in a wide variety of fields. The complexity of processes for preparing such particles is even greater when the particle to be formed is to be used in delicate biological applications, because then several parameters, which are not easy to handle, should be taken into account, such as types of chemical interactions between the different layers composing the microspheres, as well as the relevant function of the particle within the planned biological application.
Applying coating techniques for polymeric microspheres involves difficulties which do not exist in coating processes of flat surfaces, obviously due to the different physical characteristics of spherical systems. For instance, although techniques based on sol-gel procedures for the preparation of silica are well known [Stober, Fink & Bohn, Colloid Interface Sci. 26, 62 (1968), U.S. Pat. No. 5,272,240], and have been applied successfully for the preparation of a coating for a flat surface [Brinker, Hurd, Schunk, Frye and Ashley, J. of Non-Crystline Solids, 147, 424 (1992); Brinker, Frye, Hurd and Ashley, Thin Solid Films 201. 97 (1991)], the art has failed to disclose a method for coating spherical particles with silica. This silica coating is of great importance because, as will become apparent from the description to follow, it plays a major role in the construction of the desired final microsphere. The silica itself consists of particles the diameter of which is about 50 nm, and is obtained, according to sol-gel procedures, by agents such as tetraethoxysilane, [(SiOEt)4], which are converted, via hydrolysis and subsequent condensation, to silica. With respect to processes for enveloping spherical systems of submicron size, prior art mainly discloses methods for coating inorganic microspheres (made of titania, for example) with polyurea or aluminum oxide [Mayville, Partch and Matijevic, J. Colloid Interface Sci. 120 , 135 (1987); Kratohvil and Matijevic, Adv. Ceram. Mater. 2, 798 (1987); Grag and Mateijevic, Langmuir 4, 38 (1988); Aiken and Matijevic, J. Colloid Interface Sci. 126, 243 (1988)]. However, processes described by the prior art, through which organic microspheres are coated, are unsatisfactory and limited, from several aspects: the microsphere is of diameter of only 0.1 .mu.m to 0.3 .mu.m, and is composed only of cationic polystyrene. Furthermore, in all these processes the coating is made of inorganic material, namely, yttrium basic carbonate. Thus, Although hollow yttrium microspheres were further obtained by burning off the core of the described cationic polystyrene coated particles, this characteristic, namely, the inorganic nature of the coating, clearly limits the scope of the fields in which these systems can be applied, Because, as can be learned from the present invention, the interaction between the coating and various ligands is of great importance. The type of the coating plays therefore a major role. [Kawahashi and Matijevic, J. Colloid Interface Sci. 138, 534 (1990); Kawahashi Matijevic, J. Colloid Interface Sci. 143, 103 (1991); Matijevic, Langmuir 10, 8 (1994)].
Another important type of coating is one exhibiting magnetic properties. A method for the preparation of ferrite plating of various chemical compositions is known in the art [Abe et al., J. of Applied Physics 57, pp. 3795-3797, (1985)], yet this method is characterized by several disadvantages and limitations. First of all, an essential condition for the formation of the ferrite film is the presence of hydroxyl groups on the substrate to be coated, because these groups enhance the adhesion of the film to the surface. Furthermore, according to this method, if the microsphere diameter is smaller than 0.5 .mu.m, a continued magnetic coating can not be obtained. Finally, Abe et al. failed to disclose means for the protection of the ferrite coating, in order to avoid a partial leakage of the ferrite into the solution.
The present invention provides processes for the production of microspheres characterized by several desired properties:
a) It provides a process for the preparation of silica coating to spherical particles, wherein surfactants of proper nature, adsorbed on the microspheres, serves as a "connective glue" between the microsphere and the silica nanoparticles; PA1 b) It provides a process for the preparation of a microsphere coated with a magnetic layer; PA1 c) It provides a process for the preparation of hollow silica microspheres; PA1 d) It provides a process for the preparation of magnetic microspheres enveloped with silica layers; PA1 e) It allows a further modification of the surface of the solid or hollow microspheres, which are coated by magnetic layers and silica layers, to adjust them to several biological applications.